RESEARCH ACCOMPLISHMENTS NOMID and DIRA STUDIES: 1. We analyzed 5 year outcome data in 20 patients and 3 year outcome data in 26 patients with NOMID who have been receiving escalating doses of anakinra. The initially observed good clinical response to anakinra persists, The drug is overall well tolerated. In most patients hearing and vision was preserved over 3 and 5 years, however patients who experienced hearing loss on anakinra had already significant hearing loss at baseline and more persistent enhancement on MRI. Low grade leptomeningeal inflammation was seen in up to 50% of patients at 3 years but dropped further at 5 years. Although no new bone lesions occurred with anakinra treatment, preexisting bony lesions continued to expand on treatment. These data suggest that treatment with anakinra not only controls disease symptoms and inflammatory blood markers but can also prevent the progression of organ damage. Studies to assess the prevention of any organ damage in very young children continue. 2. The treatment of NOMID patients using the long acting IL-1 inhibitor canakinumab provided evidence of the need of higher doses to control CNS inflammation in NOMID. Final data analysis is almost complete. 3. In addition to the known founder mutations in DIRA, in Newfoundland, Holland, Puerto Rico and Lebanon, in a collaborative study we identified a novel founder mutation in 2 patients from Brazil, a 15 basepair in frame deletion, that leads to the encoding of a nonfunctional protein; and a nonsense mutation in 2 affected siblings from Turkey in collaboration with a group from Turkey. 4. Preliminary analyses of long-term outcomes in patients with DIRA treated with IL-1 blocking (anakinra) therapies indicates good inflammatory control and prevention of organ damage in nine patients. CANDLE and CAMPS studies: 1. We identified the genetic cause of Chronic atypical neutrophilic dermatosis with lipodystrophy, and elevated temperature (CANDLE) and described IFN activation as a prominent dysregualted pathway in peripheral blood, which suggested that abnormal interferon production may lead to the inflammatory manifestations of the disease and led to the development of a compassionate use study with a drug that can inhibit interferon signaling, a JAK1,2 inhibitor in patients with CANDLE. CANDLE patients are unresponsive to IL-1 blocking therapy and have incomplete responses to blocking TNF and IL-6. In an international collaboration, we investigated the clinical phenotype, genetic cause and the immune dysregulation in nine CANDLE patients effort. CANDLE is caused by mutations in PSMB8, a gene that encodes a protein degrading complex, called, immuno-proteasome. Although 7 patients were homozygous for the missense mutations in PSMB8 (c.224C>T and c.405C>A), two patients were heterozygous for a PSMB8 mutation and one patient is mutation negative for PSMB8 mutations, suggesting genetic heterogeneity. Mutations in PSMB8 were found concomitantly in adult patients clinically described as JMP (joint contractures, muscle atrophy and panniculitis induced lipodystrophy) syndrome in the US and Nakajo Nishimura syndrome (NNS) in Japan. The detection of mutations in the same gene in these disorders broadened the clinical understanding of the disease spectrum that is associated with these proteasome mutations and showed that the early onset in our pediatric patients indicates a severe disease presentation early in life. Our studies extend the clinical and pathogenic description of this novel autoinflammatory syndrome. Functional studies showed that mutation-positive and mutation-negative patients expressed high IP-10 (Interferon gamma-induced protein 10) levels. Levels of MCP-1, IL-6, and IL-1Ra were moderately elevated. Microarray profiles and monocyte stat-1 activation suggested a unique interferon (IFN) signaling signature, unlike in the IL-1 mediated autoinflammatory disorders where IPP-10 levels are only borderline elevated. These observations led to the hypothesis that IFN may be a key inflammatory mediator of the inflammatory disease manifestations in CANDLE. 2. CAMPS studies: The molecular diagnosis of CARD14 mediated pustulosis (CAMPS) led to the better understanding of the role of keratinocytes in triggering skin inflammation. Autosomal dominant mutations in G117S and c.3495G>A (altered splice site) in exons 3 and 4 of CARD14 cause autosomal dominant psoriasis. A de novo CARD14 mutation, G138A, was detected in one of our patients with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the G117S and G138A substitutions lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokines, (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis. UNDIFFERENTIATED AUTOINFLAMMTORY DISEASES We continue to follow and describe the inflammatory disease manifestations in patients with genetically not yet defined autoinflammatory diseases. CONCLUSIONS AND SIGNIFICANCE 1. IL-1 blocking therapies have become the standard of treatment for patients with CAPS and DIRA and other autoinflammatory diseases with clinical similarities to the genetic IL-1 diseases. We continue to evaluate the long term safety and efficacy with these agents in our protocols. We are in the process of investigating whether long acting IL-1 blocking agents will also have a role in the treatment of DIRA. The understanding of the pathogenesis of these disorders continues to provide key insights into the regulation of IL-1 as a key inflammatory cytokine that may have a role beyond NOMID and DIRA and may play a role in disorders such as Type 2 diabetes, gout, obesity and coronary artery disease. 2. Long-term treatment with IL-1 blocking therapy indicates that treatment of patients with NOMID is safe and effective over 5 years after initiation of treatment. Anakinra treatment improves disability and retards/stops progression of hearing loss and vision loss. 3. Treatment with long acting IL-1 inhibitors may allow for more convenient treatment options, particularly in children in whom daily injections can be difficult. A study evaluating the efficacy of the long acting IL-1 inhibitor canakinumab in patients with NOMID indicates control of systemic inflammation and disease signs and symptms, but raises the question about the degree of CNS inflammation that can be achieved in patients with severe disease. 4. The evaluation of IL-1 blockade unresponsive patients led to the discovery of a novel autoinflammatory diseases, CANDLE also called JMP, and NNS are caused by mutations in PSMB8, a gene encoding for a component of an immunoproteasome. The identification of a molecular defect in the protein processing machinery of a cell and our investigations regarding an inflammatory mechanism responsible for the disease phenotype will allow us to explore additional targets in the treatment of these patients. The prominence of an interferon signature may provide such a target for treatment. Validation in the context of a treatment study is ongoing. 7. The discovery that mutations in CARD14 cause CARD14 mediated pustulosis (CAMPS) points to the role of keratinocytes in triggering the inflammatory response.